Intravenously administered AL 002 was safe and generally well tolerated in cynomolgus monkey toxicology studies, up to 250 mg/kg weekly dose for 4 weeks. No adverse findings were observed. The no observed adverse effect level (NOAEL) was 250 mg/kg  .
In the single ascending dose (SAD) portion of the phase I INVOKE study in healthy volunteers (n=64), AL 002 was generally well tolerated with no drug-related serious adverse events or dose-limiting toxicities up to the highest dose    .
After multiple weekly dosing in cynomolgus monkeys, systemic exposure of intravenously administered AL 002 increased slightly less than dose proportionally with increasing doses. Some accumulation of AL 002 was observed. The ratio of serum and CSF levels of AL 002 appeared consistent across the three doses tested. A dose dependent effect on pharmacodynamic biomarkers in both serum and CSF was observed  .
In preclinical study conducted in mouse models of Alzheimer’s disease (expressing either the common variant or the R47H variant of human TREM2), expansion of unique subpopulations of metabolically active and proliferating microglia was observed post treatment with a single injection of AL002c (a variant of AL002). Prolonged treatment with AL002c, reduced neuronal damage, tempered the microglial inflammatory response and reduced the formation of toxic filamentous plaques, which curtailed neurite dystrophy. Treatment with AL002c was beneficial after plaque formation, suggesting that anti-TREM2 antibodies may be helpful even if introduced at relatively late stages of disease. Improved cognitive and behavioral outcomes were exhibited by the treated mice versus the placebo control. Antibody-mediated engagement of TREM2 enhanced neuroprotective microglia. the peripheral injection of antibodies triggered TREM2 signaling microglial proliferation and activation in mouse brains. These data suggested that the antibodies efficiently cross the blood-brain barrier and that TREM2 signal induction was sufficient to shift the microglia phenotype. In 5xFAD mice, chronic treatment with a TREM2 agonist caused increased expression of synaptic and myelin genes. Administration of AL 002 activated microglia and increased clustering of microglia around amyloid plaques in 5xFAD mice models. Also a reduced amyloid deposition and improved cognition was reported with AL 002 in mice model    .
In the single ascending dose (SAD) portion of the phase I INVOKE study in healthy volunteers (n=64), AL 002 decreased sTREM2 in cerebral spinal fluid (CSF), in a dose-dependent manner, demonstrating proof of target engagement in the brain. Treatment of healthy volunteers with AL 002 caused an increase in CSF levels of CSF1R, SPP1 and IL1RN in a dose-dependent manner   .